Functional characterisation of the human cloned 5-HT7 receptor (long form); antagonist profile of SB-258719
Version of Record online: 11 FEB 2009
1998 British Pharmacological Society
British Journal of Pharmacology
Volume 124, Issue 6, pages 1300–1306, July 1998
How to Cite
Thomas, D. R., Gittins, S. A., Collin, L. L., Middlemiss, D. N., Riley, G., Hagan, J., Gloger, I., Ellis, C. E., Forbes, I. T. and Brown, A. M. (1998), Functional characterisation of the human cloned 5-HT7 receptor (long form); antagonist profile of SB-258719. British Journal of Pharmacology, 124: 1300–1306. doi: 10.1038/sj.bjp.0701946
- Issue online: 11 FEB 2009
- Version of Record online: 11 FEB 2009
- (Received February 16, 1998, Revised April 4, 1998, Accepted April 20, 1998)
- Human 5-HT7(a) receptor;
- long splice variant;
- functional characterisation;
- adenylyl cyclase;
- [3H]-5-CT binding;
- constitutive receptor activity;
- inverse agonism;
- 1The functional profile of the long form of the human cloned 5-HT7 receptor (designated h5-HT7(a)) was investigated using a number of 5-HT receptor agonists and antagonists and compared with its binding profile. Receptor function was measured using adenylyl cyclase activity in washed membranes from HEK293 cells stably expressing the recombinant h5-HT7(a) receptor.
- 2The receptor binding profile, determined by competition with [3H]-5-CT, was consistent with that previously reported for the h5-HT7(a) receptor. The selective 5-HT7 receptor antagonist SB-258719 ((R)-3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzene sulfonamide) displayed high affinity (pKi 7.5) for the receptor.
- 3In the adenylyl cyclase functional assay, 5-CT and 8-OH-DPAT were both full agonists compared to 5-HT and the rank order of potency for agonists (5-CT>5-HT>8-OH-DPAT) was the same in functional and binding studies.
- 4Risperidone, methiothepin, mesulergine, clozapine, olanzapine, ketanserin and SB-258719 antagonised surmountably 5-CT-stimulated adenylyl cyclase activity. Schild analysis of the antagonism by SB-258719 gave a pA2 of 7.2±0.2 and slope not significantly different from 1, consistent with competitive antagonism.
- 5The same antagonists also inhibited basal adenylyl cyclase activity with a rank order of potency in agreement with those for antagonist potency and binding affinity. Both SB-258719 and mesulergine displayed apparent partial inverse agonist profiles compared to the other antagonists tested. These inhibitory effects of antagonists appear to be 5-HT7 receptor-mediated and to reflect inverse agonism.
- 6It is concluded that in this expression system, the h5-HT7(a) receptor shows the expected binding and functional profile and displays constitutive activity, revealing inverse agonist activity for a range of antagonists.
British Journal of Pharmacology (1998) 124, 1300–1306; doi:10.1038/sj.bjp.0701946